Quinazolinone, quinolone and related analogs as sirtuin modulators
Provided herein are novel sirtuin-modulating compounds and methods of use thereof. The sirtuin-modulating compounds may be used for increasing the lifespan of a cell, and treating and/or preventing a wide variety of diseases and disorders including, for example, diseases or disorders related to aging or stress, diabetes, obesity, neurodegenerative diseases, cardiovascular disease, blood clotting disorders, inflammation, cancer, and/or flushing as well as diseases or disorders that would benefit from increased mitochondrial activity. Also provided are compositions comprising a sirtuin-modulating compound in combination with another therapeutic agent.
1. A compound of Formula (IIA) or Formula (IIB):
wherein:
each R 9 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 13 )(R 13 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 13 )(R 13 ), and —N(R 13 )(R 13 );
R 11 is selected from a carbocycle and a heterocycle;
wherein:
R 11 is optionally substituted with one to two substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ≡O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 4 alkyl, —O—R 13 , —S—R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ); and when R 11 is phenyl, R 11 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, —O-(saturated heterocycle), fluoro-substituted-O-(saturated heterocycle), or C 1 -C 4 alkyl-substituted —O-(saturated heterocycle);
wherein:
each R 13 is independently selected from hydrogen, and —C 1 -C 4 alkyl; or
two R 13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected from N(R 13 ), S, S(═O), S(═O) 2 , and O, wherein
when R 13 is alkyl, the alkyl is optionally substituted with one or more —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; and
when two R 13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at a carbon atom with —OH, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 , and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;
R 12 is selected from a carbocycle and a heterocycle other than tetrazolyl;
wherein:
R 12 is optionally substituted with one to two substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —S—R 13 , —S(O)—R 13 , —S(O) 2 —R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), —O-phenyl, phenyl, and a second heterocycle, and
when R 12 is phenyl, R 12 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy, or —O-(saturated heterocycle);
wherein:
any phenyl, second heterocycle or saturated heterocycle portion of a substituent of R 12 is optionally substituted with halo; —C≡N; C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl and —N—(C 1 -C 4 ) 2 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoro-substituted alkyl, C 1 -C 4 alkyl-N(R 13 )(R 13 ), C 1 -C 4 alkyl-C(O)—N(R 13 )(R 13 ), C 1 -C 4 alkyl-O—R 13 , and C 1 -C 4 alkyl-NR 13 —C(O)R 13 ;
X 1 is selected from —NH—C(═O)-†, —C(═O)—NH-†, or —NH—S(═O) 2 -†;
wherein:
† represents where X 1 is bound to R 11 ; and
each R 15 and R 16 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 and (C 1 -C 3 alkyl)-CF 3 ; or
a pharmaceutically acceptable salt thereof.
2. The compound of claim 1 , wherein X 1 is selected from —NH—C(O)-† or —C(O)—NH-†.
3. The compound of claim 1 , wherein R 11 is selected from:
wherein R 11 is optionally substituted with one or two substituents independently selected from halo, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), ═O, —N(R 13 )(R 13 ), and —O—R 13 .
4. The compound of claim 3 , wherein R 11 is selected from:
5. The compound of claim 4 , wherein R 11 is selected from
6. The compound of claim 1 , wherein R 12 is selected from:
wherein:
R 12 is optionally substituted with one or two groups independently selected from halo, C 1 -C 4 alkyl, —(C 1 -C 4 alkyl)-N(R 14 )(R 14 ), C 1 -C 2 fluoro-substituted alkyl, —O—R 14 , —SO 2 —R 14 , —N(R 14 )(R 14 ), and —O—(C 1 -C 4 alkyl)-N(R 14 )(R 14 ).
7. The compound of claim 6 , wherein R 12 is selected from:
8. The compound of claim 7 , wherein R 12 is selected from
9. A compound which is:
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or a pharmaceutically acceptable salt thereof.
10. A compound which is selected from any one of the Compounds from the following table:
Compound
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Structure
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or a pharmaceutically acceptable salt thereof.
11. A compound which is selected from the following table:
Compound
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Structure
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or a pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a compound of claim 1 or a pharmaceutically acceptable salt thereof and pharmaceutically acceptable excipient, carrier or diluent.
13. A method for treating insulin resistance, a metabolic syndrome, diabetes, or complications thereof, or for increasing insulin sensitivity in a subject, comprising administering a pharmaceutical composition of claim 12 to a subject in need thereof.
14. A compound of Formula (IIB):
wherein:
each R 9 is independently selected from hydrogen, halo, —C≡N, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, C 1 -C 4 alkyl, —S—(C 1 -C 4 ) alkyl, C 3 -C 7 cycloalkyl, —(C 1 -C 2 ) alkyl-N(R 13 )(R 13 ), —O—CH 2 CH(OH)CH 2 OH, —O—(C 1 -C 3 ) alkyl-N(R 13 )(R 13 ), and —N(R 13 )(R 13 );
R 11 is selected from a carbocycle and a heterocycle;
wherein:
R 11 is optionally substituted with one to two substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, ═O, C 3 -C 7 cycloalkyl, fluoro-substituted C 1 -C 4 alkyl, —O—R 13 , —S—R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), and —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 )—; and when R 11 is phenyl, R 11 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, fluoro-substituted 3,4-ethylenedioxy, —O-(saturated heterocycle), fluoro-substituted-O-(saturated heterocycle), or C 1 -C 4 alkyl-substituted —O-(saturated heterocycle);
wherein
each R 13 is independently selected from hydrogen, and —C 1 -C 4 alkyl; or
two R 13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle optionally comprising one additional heteroatom selected from N(R 13 ), S, S(═O), S(═O) 2 , and O, wherein
when R 13 is alkyl, the alkyl is optionally substituted with one or more —OH, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 ; and
when two R 13 are taken together with the nitrogen atom to which they are bound to form a 4- to 8-membered saturated heterocycle, the saturated heterocycle is optionally substituted at a carbon atom with —OH, —C 1 -C 4 alkyl, fluoro, —NH 2 , —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl) 2 , —NH(CH 2 CH 2 OCH 3 ), or —N(CH 2 CH 2 OCH 3 ) 2 , and optionally substituted at any substitutable nitrogen atom with —C 1 -C 4 alkyl, fluoro-substituted C 1 -C 4 alkyl, or —(CH 2 ) 2 —O—CH 3 ;
R 12 is selected from a carbocycle and a heterocycle other than tetrazolyl;
wherein:
R 12 is optionally substituted with one to two substituents independently selected from halo, —C≡N, C 1 -C 4 alkyl, C 3 -C 7 cycloalkyl, C 1 -C 2 fluoro-substituted alkyl, —O—R 13 , —S—R 13 , —S(O)—R 13 , —S(O) 2 —R 13 , —(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —N(R 13 )(R 13 ), —O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-O—(C 1 -C 4 alkyl)-N(R 13 )(R 13 ), —C(O)—N(R 13 )(R 13 ), —(C 1 -C 4 alkyl)-C(O)—N(R 13 )(R 13 ), —O-phenyl, phenyl, and a second heterocycle, and
when R 12 is phenyl, R 12 is also optionally substituted with 3,4-methylenedioxy, fluoro-substituted 3,4-methylenedioxy, 3,4-ethylenedioxy, or fluoro-substituted 3,4-ethylenedioxy, or —O-(saturated heterocycle);
wherein:
any phenyl, second heterocycle or saturated heterocycle portion of a substituent of R 12 is optionally substituted with halo; —C≡N; C 1 -C 4 alkyl, fluoro-substituted C 1 -C 2 alkyl, —O—(C 1 -C 2 ) fluoro-substituted alkyl, —O—(C 1 -C 4 ) alkyl, —S—(C 1 -C 4 ) alkyl, —S—(C 1 -C 2 ) fluoro-substituted alkyl, —NH—(C 1 -C 4 ) alkyl and —N—(C 1 -C 4 ) 2 alkyl;
R 14 is selected from hydrogen, C 1 -C 4 alkyl, C 1 -C 4 fluoro-substituted alkyl, C 1 -C 4 alkyl-N(R 13 )(R 13 ), C 1 -C 4 alkyl-C(O)—N(R 13 )(R 13 ), C 1 -C 4 alkyl-O—R 13 , and C 1 -C 4 alkyl-NR 13 —C(O)R 13 ;
X 1 is selected from —NH—C(═O)-†, —C(═O)—NH-†; wherein:
† represents where X 1 is bound to R 11 ; and
each R 15 and R 16 is independently selected from hydrogen, C 1 -C 4 alkyl, —CF 3 and (C 1 -C 3 alkyl)-CF 3 ; or
a pharmaceutically acceptable salt thereof.
15. A compound which is:
Compd
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Structure
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or a pharmaceutically acceptable salt thereof.
16. A compound which is:
Compd
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Structure
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or a pharmaceutically acceptable salt thereof.